Functional analysis of PCSK2 coding variants: A founder effect in the Old Order Amish population

Abstract

Aims In humans, noncoding variants of PCSK2, the gene encoding prohormone convertase 2 (PC2), have been previously associated with risk for and age of onset of type 2 diabetes (T2D). The aims of this study were to identify coding variants in PCSK2; to determine their possible association with glucose handling; and to determine functional outcomes for coding variants in biochemical studies. Methods Exome-wide genotyping was performed on 1725 Old Order Amish (OOA) subjects. PCSK2 coding variants were tested for association with diabetes-related phenotypes. In vitro analyses using transfected human PC2-encoding constructs were performed to determine the impact of each mutation on PC2 activity. Results We identified 10 rare missense coding variants in PCSK2 in various genomic databases. R430W (rs200711626) is greatly enriched in the OOA population (MAF 4.3%). This variant is almost twice as common (MAF 7.4%) in OOA individuals with T2D as in OOA individuals with normal or with normal/impaired glucose tolerance (MAF 3.9% and 2.9%, respectively; p= 0.25 and p=0.10). In vitro experiments revealed a broadening of the pH optimum for the R430W variant, which may result in increased activity against PCSK2 substrates. Conclusions Although the association of the R430W variation with T2D in the OOA population did not reach significance, based upon the broadened pH profile of R430W PC2, we speculate that the presence of this substitution may result in altered processing of PCSK2 substrates, ultimately leading to increased conversion to diabetes.

Islet prohormone processing in health and disease

“…Order Amish population (R430W variant rs200711626). 23 Although not significant (likely due to low power from infrequency of the allele), R430W was almost twice as prevalent in T2D individuals within this population. Further characterization of this allele found no difference in enzymatic activity or secretion, although R430W did broaden the PC2 pH optimum suggesting it induces a mild conformational change.…”

“…PCSK2 polymorphisms may not be as well characterized as PCSK1 polymorphisms due in part to the rarity of PCSK2 protein‐coding variants. A non‐synonymous PCSK2 variant was found enriched in an Old Order Amish population (R430W variant rs200711626) . Although not significant (likely due to low power from infrequency of the allele), R430W was almost twice as prevalent in T2D individuals within this population.…”

Loss of Furin in β-Cells Induces an mTORC1-ATF4 Anabolic Pathway That Leads to β-Cell Dysfunction

“…In addition, common heterozygous PC1/3 mutations that cause partial loss of function contribute to variations in human BMI and plasma proinsulin and are associated with impaired regulation of plasma glucose levels (5). Genome-wide association studies have found associations between several common variants in the gene encoding human PC2 and diabetes risk and related traits in human populations (6,7).…”

Loss of hypothalamic Furin affects POMC to proACTH cleavage and feeding behavior in high-fat diet-fed mice

“…In addition, several polymorphisms and rare heterozygous mutations in the human PCSK1 gene (encoding for PC1/3) have been associated with an increased risk of obesity [ [14] , [15] , [16] ]. So far there are no reported PCSK2 (encoding for PC2) null patients, but several studies have associated PCSK2 SNPs with type 2 diabetes risk [ [17] , [18] , [19] ]. In this regard, Pcsk2 knockout mice have chronic mild hypoglycemia and hyperplasia of the pancreatic α-cells [ 20 ].…”